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Humanin and Intracerebral Hemorrhage

Award Number: R01NS111590
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Humanin and Intracerebral Hemorrhage - ABSTRACT Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke with high mortality rates, and profound morbidity and disability. The mechanisms leading to brain damage caused by ICH are multifaceted and poorly understood. There is no FDA approved treatment for ICH. Recent studies and our preliminary work indicate that astrocytes, cells known to have a uniquely dense network of mitochondria (Mt), secrete intact Mt, which upon entering adjacent neurons or microglia could help them resist injury and promote restorative function when exposed to the damage effects of intracerebral blood products. While the biology of Mt transfer is seen as homeostatic, the mechanisms behind their beneficial effect is unclear. One of the unique functions of Mt is to produce, from its own genome, a small potent bioactive secretory peptide, humanin (HN; encoded in the Mt DNA 16S ribosomal RNA region), which acts through a specific surface receptor present in the brain, including on neurons and microglia. HN is implicated in Mt-associated longevity and has cytoprotective activities. However, the mechanism behind these beneficial effects of HN in cerebrovascular diseases and its clinical relevance remains unclear. Our extensive preliminary results demonstrate: (1) a robust Mt transfer from astrocytes to neurons or to microglia and that the transfer confers cytoptotection in neurons and a “healing” phenotype in microglia under ICH-like conditions. (2) ICH-mediated injury in mice results in a profound loss of HN in the ICH-affected hemisphere and treatment with recombinant HN (rHN) significantly reduced neurological deficits produced by ICH. (3) HN or astrocytic Mt-transfer into neurons leads to (a) STAT3/MnSOD upregulation and reduction of oxidative damage to neurons, and (b) PPAR upregulation in microglia and a “healing” phenotype, including increased phagocytic capacity. Therefore, we hypothesize that Mt-derived HN, released or transferred within the intact Mt secreted from astrocytes (or injected as recombinant HN, rHN) can reduce ICH-mediated damage (1) by increasing neuronal resistance to oxidative damage (through upregulating Mt anti-oxidative Mn-SOD) and by supporting neural plasticity; and (2) by securing “healing” (phagocytic/anti-oxidative/anti-inflammatory/trophic) phenotype of microglia, through transcription factor PPAR. Our specific aims are: (1) To establish (in vitro) the cellular mechanisms by which astrocytic HN and Mt transfer (A) attenuates injury to neurons and (B) promotes the “healing” phenotype to microglia under conditions simulating ICH. (2) To determine (in vivo) the translational value and mechanism by which Mt/HN mediates protection from damage imposed by ICH. (3) To establish age/sex-related differences in Mt transfer, and HN expression by using aged male and female mice, and the therapeutic effect of HN in ICH.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $470,547 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/13/2022	NON-COMPETING CONTINUATION	$423,493
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/1/2023	NON-COMPETING CONTINUATION	$47,054
														Subtotal = $470,547

Issue Date FY: 2022 ( Subtotal = $470,547 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/12/2022	NON-COMPETING CONTINUATION	$47,054
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/6/2022	NON-COMPETING CONTINUATION	$423,493
														Subtotal = $470,547

Issue Date FY: 2021 ( Subtotal = $476,982 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/8/2021	NON-COMPETING CONTINUATION	$47,697
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/10/2020	NON-COMPETING CONTINUATION	$429,285
														Subtotal = $476,982

Issue Date FY: 2020 ( Subtotal = $472,906 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/19/2019	NON-COMPETING CONTINUATION	$425,615
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/13/2020	NON-COMPETING CONTINUATION	$47,291
														Subtotal = $472,906

Issue Date FY: 2019 ( Subtotal = $484,238 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/25/2019	NEW	$484,238
														Subtotal = $484,238

Grand Total All Awards = $2,375,220

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Humanin and Intracerebral Hemorrhage

Award Number: R01NS111590

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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